N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, also known as agomelatine, of formula I
is a melatogenic agonist of melatonin receptor 1 (MT-1) and melatonin receptor 2 (MT-2) and a 5-HT2C antagonist that is licensed as a treatment for depression or major depressive disorder.
The physicochemical properties endowed by the solid-state structure is a critical parameter in the development of solid dosage forms of pharmaceuticals as these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can potentially exist in both amorphous and crystalline forms. It is further known that for a crystalline solid various polymorphs and solvates are possible.
Polymorphism arises from the crystallisation of a substance in more than one crystalline form, each form being identical in terms of the chemical composition of the system but differing in the arrangement of molecules in the crystal lattice. It is also possible for solvent molecules to become included in the crystal structure in addition to the active pharmaceutical molecules to produce a crystalline solvate or, when the solvent is specifically water, a crystalline hydrate. It is an accepted principle that different polymorphs, solvates or hydrates of an active pharmaceutical molecule may have different physicochemical properties as a result of the differences in the number, type and strength of intermolecular interactions between the molecules in the different crystalline forms. For example, different polymorphs and solvates have been shown to differ in their solubilities, stabilities, hygroscopicities and different mechanical properties relating to qualities such as their filterability and flowability.
For active pharmaceutical molecules containing an acidic or basic functional group this principle can be exploited by the preparation of various crystalline salts of the active pharmaceutical ingredient to modulate and optimize the physicochemical properties of the obtained crystalline solid for a specific application. The changes in the physicochemical properties resulting from the inclusion of a counterion in the crystal structure are a consequence of both the molecular structure and properties of the active pharmaceutical molecule and counterion and the intermolecular interactions between the molecules in the crystal structure. It is therefore possible to change the physicochemical properties of the crystalline solid through the inclusion of different counterions, giving crystalline salts with different physicochemical properties. This is a well-established and important technique in pharmaceutical development and is standard practice in the development of new solid forms of active pharmaceutical ingredients (API).
Typical counterions used in pharmaceutical salt formation are acidic or basic molecules or ions that are considered to be pharmaceutically acceptable due to their low toxicity, well established use as food additives or their natural occurrence in the human organism. Typical examples of counterions used include carboxylic acids, sulfonic acids, hydroxy acids, amino acids and inorganic acids for basic active pharmaceutical molecules and amines, alkali metals, alkaline metals and amino acids for acidic active pharmaceutical substances.
A major limitation of salt formation is that it is inapplicable to neutral APIs. Furthermore, the range of possible counterions for weakly acidic or weakly basic APIs can be limited by the ionization constant of the acid or base groups on the molecule. Finally, it has been demonstrated that the composition of crystalline molecular salts can be highly unpredictable, particularly with regards to hydrate and solvate formation.
Faced with these limitations, the formation of pharmaceutically acceptable cocrystals of active pharmaceutical molecules offers an alternative approach to the generation of new solid forms of the active substance. In this context a cocrystal, or alternatively co-crystal, is understood to be a binary molecular crystal containing the molecules of the API together with another molecular species in a defined stoichiometric ratio where both components are in their neutral state. In this case the terms “cocrystal” and “co-crystal” are generally understood to be synonymous terms referring to such a system. The second component in the cocrystal (the component other than the active pharmaceutical ingredient) is commonly referred to as a “cocrystal former”. Pharmaceutically acceptable cocrystal formers include any molecule considered acceptable as a counterion for a pharmaceutical salt or known as a pharmaceutical excipient.
A widely accepted definition of a pharmaceutical cocrystal is a crystalline system containing an active pharmaceutical molecule and a cocrystal former that is a solid at ambient temperature and pressure in a defined stoichiometric ratio, although a cocrystal is not limited to containing only two components. The components of the cocrystal are linked by hydrogen bonding and other non-covalent and non-ionic interactions. (Aakeroy and Salmon, CrystEngComm, 2005, 439-448). This definition distinguishes cocrystals from crystalline solvates, in which case one of the components is a liquid at ambient temperature and pressure.
It is also understood that, in common with single-component crystalline systems and salts, cocrystals can also contain solvent molecules or water to form cocrystal solvates or hydrates. It is further understood that, in common with all other types of crystalline system, cocrystals are capable of existing as different packing arrangements of the same molecular components to give polymorphic forms of a particular cocrystal.
In common with other types of crystalline system, particularly crystalline salts, it is currently impossible to predict ab initio which combination of active pharmaceutical compound and cocrystal former will crystallize as a cocrystal or its crystal structure. Furthermore it is impossible to predict the physicochemical properties of a cocrystal either from the molecular structures of the component molecules or from the crystal structure of the cocrystal if this is known. As a result the discovery and selection of an appropriate cocrystal form of an active pharmaceutical compound to satisfy particular physicochemical property requirements is a non-trivial process and the ideal cocrystal form is not obvious from the outset.
N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide is classified as a high solubility drug in accordance with the BCS classification system and a criteria for the selection of a suitable cocrystal form will be that it displays bioequivalence to the marketed single component form of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide. A new cocrystal, as for a new polymorph, salt or hydrate, may be endowed with physicochemical properties that offer an advantage over the current marketed solid form if the new cocrystal shows superior stability of the chemical or solid form under storage conditions, reproducibility and purity of the solid form obtained to ensure consistency in the efficacy of the drug product manufactured or mechanical properties or physical characteristics that improve the processability and manufacturability of the solid form.
The identification of crystalline forms may be a non-trivial process and the use of complementary techniques including X-Ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and vibrational spectroscopy (for example Raman spectroscopy) is advisable to clearly and unambiguously identify the crystalline form obtained. X-ray powder diffraction is the routine method for unambiguously characterising crystalline phases and, after suitable calibration, assessing phase purity. Single-crystal X-ray diffraction is the optimum method for characterizing a crystalline solid, enabling the determination of the crystallographic unit cell and the chemical identity, molecular conformation and stoichiometry of the molecules in the crystal structure and their intermolecular interactions. However, its requirement for relatively large and high-quality single crystals restricts the use of this technique to systems capable of producing suitable crystalline material and hence this is not a routinely employed method.
A recent paper (Crystal Growth and Design, 2011, pages 466-471) described two binary crystalline systems containing agomelatine with acetic acid and ethylene glycol. Given that both ethylene glycol and acetic acid are liquids at ambient temperature and pressure the two systems described do not meet the criteria for cocrystals given above and are arguably solvates. In any case, both these systems have drawbacks for use in a pharmaceutical formulation. Ethylene glycol is not considered to be pharmaceutically acceptable. Whilst acetic acid is pharmaceutically acceptable the crystallisation of the system in the article was performed by slow vapor diffusion. Although this is a sensible method for the laboratory-scale crystallization of diffraction-quality single crystals it is not practicable for the crystallisation of the quantities of material routinely required for pharmaceutical production. Moreover, their melting points are low enough to risk problems in pharmaceutical manufacturing. Therefore the development of other stable pharmaceutically acceptable cocrystals that can be obtained robustly and reproducibly using scalable crystallisation procedures is highly desirable.